Abstract
Targeting tumors by means of their vascular endothelium is a promising strategy, which utilizes targets that are easily accessible, stable, and do not develop resistance against therapeutic agents. Folate receptor is a highly specific tumor marker, frequently over expressed in cancer tumors. In the present study, an active drug delivery system, which can effectively target cancer cells by means of folate receptor-mediated endocytosis, have ability to escape from opsonization and capability of magnetic targeting to withstand the drag force of the body fluid have been designed and synthesized. The core of the drug delivery system is of mono-domain magnetic particles of magnetite. Magnetite nanoparticles are shielded with PEG, which prevents their phagocytosis by reticuloendothelial system. These PEG shielded magnetite nanoparticles are further decorated with an antitumor receptor—folic acid and loaded with an antineoplastic agent doxorubicin. An in vitro drug loading and release kinetics study reveals that the drug delivery system can take 52 % of drug load and can release doxorubicin over a sustained period of 7 days. The control and sustained release over a period of several days may find its practical utilities in chemotherapy where frequent dosing is not possible.
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References
Barrera C, Herrera A, Zayas Y, Rinaldi C (2009) Surface modification of magnetite nanoparticles for biomedical applications. J Magn Magn Mater 321:1397–1399
Brannon-Peppas L, Blanchette J (2004) Nanoparticles and targeted systems for cancer therapy. Adv Drug Del Rev 56:1649–1659
Caliceti P, Salmaso S, Semenzato A, Carofiglio T, Fornasier R, Fermeqlia M, Ferrone M, Pricl S (2003) Synthesis and physicochemical characterization of folate: cyclodextrin bioconjugate for active drug delivery. Bioconjugate Chem 14:899–908
Cascante M, Centelles J, Veech R, Lee W, Boros L (2000) Role of thiamin (Vitamin B1) and transketolase in tumor cell proliferation. Nutr Cancer 36:150–154
Dreborg S, Akerblom E (1990) Immunotherapy with monomethoxypolyethelene glycol modified allergens. Crit Rev Ther Drug Carrier Sys 63:15–365
Fornari F, Randolph J, Yalowich J, Ritke M, Gewirtz D (1994) Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 45:649–656
Gupta A, Gupta M (2005) Synthesis and surface engineering of iron oxide nanoparticles for biomedical applications. Biomaterials 26:3995–4021
Harris J (1985) Laboratory synthesis of polyethelene glycol derivatives. J Macromol Sci, Rev Macromol Chem Phys C25:325–373
Kaul G, Amiji M (2002) Long-circulating poly (ethylene glycol)-modified gelatin nanoparticles for intracellular delivery. Pharm Res 19:1061–1067
Kiessling L, Gestwicki J, Strong L (2000) Synthetic multivalent ligands in the exploration of cell-surface interactions. Curr Opin Chem Biol 4:696–703
Koda J, Venook A, Walser E, Goodwin S (2002) Phase I/II trial of hepatic intraarterial delivery of doxorubicin hydrochloride adsorbed to magnetic targeted carriers in patients with hepatocarcinoma. Eur J Cancer 38:S18
Komaki R, Putnam J, Cox J (1997) Thymic neoplasms. Curr Opin Oncol 9:156–160
Lee K (2005) Stability of Ionic complexes prepared from plasmid DNA and self-aggregated chitosan nanoparticles. Macromol Res 13:542–544
Li Y, Afzaal M, Brien P (2006) The synthesis of ammine-capped magnetic (Fe, Mn, Co., Ni) oxide nanocrystals and their surface modification for aquous dispersibility. J Mater Chem 16:2175–2180
Lin C, Chiang RJ, Sung T (2006) Magnetic nanoproperties of monodispersed iron oxide nanoparticles. J App Phys 99: 08N710
Lopez-Quintela M, Rivas J (1993) Chemical reactions in microemulsions: a powerful method to obtain ultrafine particles. J Coll Interface Sci 158:446–451
Luangtana-anan M, Nunthanid J, Limmatvapirat S (2010) Effect of molecular weight and concentration of polyethylene glycol on physicochemical properties and stability of shellac film. J Agric Food Chem 58:12934–12940
Lübbe AS, Bergemann C, Huhnt W, Fricke T, Riess H, Brock JW, Huhn D (1996) Preclinical experiences with magnetic drug targeting: tolerance and efficacy. Cancer Res 56:4694–4701
Lübbe A, Alexiou C, Bergmann C (2001) Clinical applications of magnetic drug targeting. J Surg Res 95:200–206
Ma M, Zhang Y, Yu W, Shen H, Zhang H, Gu N (2003) Preparation and characterization of magnetite nanoparticles coated by amino silane. J Colloids surf A: 212–219
Maed H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 65:271–284
Mohapatra S, Mallick S, Maiti T, Ghosh S, Pramanik P (2007) Synthesis of highly stable folic acid conjugate magnetite nanoparticles for targeting cancer cells. Nanotechnology 18:385102
Pankhurst Q, Connolly J, Jones S, Dobson J (2003) Applications of magnetic nanoparticles in biomedicine. J Phys D 36:R167–R181
Park J, An K, Hwang Y, Park J, Noh H, Kim J, Park J, Hwang N, Hyeon T (2004) Ultra-large-scale syntheses of monodisperse nanocrystals. Nature Mater 3:891–895
Plank C (2009) Nanomedicine: silence the target. Nat Nanotechnol 4:544–545
Prozorov T, Prozorov R, Koltypin Yu, Felner I, Gedanken A (1998) Sonochemistry under an applied magnertic field: determining the shape of a magnetic particle. J Phys Chem B 102:10165–10168
Reddy J, Allagadda V, Leamon C (2005) Targeting therapeutics and imaging agents to folate receptor positive tumors. Curr Pharm Biotechnol 6:131–150
Sahoo S, Labhasetwar V (2003) Nanotech approaches to drug delivery and imaging. Drug Discov Today 8:1112–1120
Sugimoto T, Matijevic E (1980) Formation of uniform spherical magnetite particles by crystalization from ferrus hydroxyde gels. J Coll Interface Sci 74:227–243
Sun S, Zeng H (2002) Size controlled synthesis of magnetite nanoparticles. J Am Chem Soc 124:8204–8205
Sun S, Zeng H, Robinson D, Raoux S, Rice P, Wang S, Li G (2004) Monodispersed MFe2O4 (M = Fe, Co., Mn)nanoparticles. J Am Chem Soc 126:273–279
Sun C, Sze R, Zhang M (2006) Folic acid-PEG conjugated superparamagnetic nanoparticles for targeted cellular uptake and detection by MIR. J Biomed Mater Res, Part A 78A:550–557
Takakura Y, Maruyama K, Yokoyama M (1999) Passive targeting of drugs. Drug Deliv Syst 14:425–426
Tang Z, Sorensen C, Klabunde K, Hadjipanayiss G (1991) Preparation of manganese ferrite fine particles from aqueous solution. J Coll Interface Sci 146:38–52
Wilson M, Kerlan R, Fidleman N (2004) Hepatocellular carncinoma: regional therapy with a magnetic targeted carrier bound to doxorubicin in a dual MR imaging/conventional angiography suite- initial experience with 4 patients. Radiology 230:287–293
Xie J, Peng S, Brower N, Pourmand N, Wang S, Sun S (2006) One-pot synthesis of monodisperse iron oxide nanoparticles for potential biomedical applications. Pure Appl Chem 78:1003–1014
Xu Q, Xubu JinC (2005) Self-aggregates of cholic acid hydrazide-dextran conjugates as drug carriers. J Appl Polymer Sci 95:487–493
Ye X, Daraio C, Wang C, Talbot J, Jin S (2006) Room temperature solvent free synthesis of monodisperse magnetite nanocrystals. J Nanosci Nanotechnol 6:852–856
Yokoyama M, Okano T (1996) Targetable drug carriers: present status and a future perspective. Adv Drug Deliv Rev 21:77–80
Zhang J, Misra R (2007) Magnetic drug-targeting carrier encapsulated with thermosensitive smart polymer: core-shell nanoparticles carriers and drug release response. Acta Biomater 3:838–850
Zhang J, Srivastava R, Misra R (2007) Core-shell magnetite nanoparticles surface encapsulated with smart stimuli-responsive polymer: synthesis, characterization, and LCST of viable drug- targeting delivery systems. Langmuir 23:6342–6351
Zhang J, Rana S, Srivastava R, Misra R (2008) On the chemical synthesis and drug delivery response of folate receptor-activated, polyethylene glycol functionalized magnetic nanoparticles. Acta Biomater 4:40–48
Acknowledgments
This work was financially supported by the Department of Science & Technology, New Delhi, under its fast track scheme SR/FTP/PS-109/2010, University Grants Commission, New Delhi under the DS Kothari postdoctoral fellowship awarded to Dr. N. Andhariya (F.4-2/2006(BSR)/13-467/2011(BSR) and Thapar University, Patiala.
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Andhariya, N., Upadhyay, R., Mehta, R. et al. Folic acid conjugated magnetic drug delivery system for controlled release of doxorubicin. J Nanopart Res 15, 1416 (2013). https://doi.org/10.1007/s11051-013-1416-9
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DOI: https://doi.org/10.1007/s11051-013-1416-9